Principal Investigator: Dr Stefano Masi

1a: Observational studies suggest that inflammation increases the risk of dementia and cognitive impairment. However, whether inflammation is cause or consequence of poor cognitive function remains unknown. Many genetic variants produce lifelong differences in the circulating levels of inflammatory markers. These genetic variants can be used to form scores which can inform on the cumulative impact of each inflammatory marker on cognition. In this project, the association of the genetic scores affecting circulating levels of inflammatory markers with cognitive function will be investigated to assess whether inflammation is causally relayed to higher risk of cognitive impairment.

1b: This research proposal perfectly fits with the UK Biobank’s stated purpose as it is based on a novel research approach intended to increase understanding of the mechanisms and molecular pathways leading to cognitive impairment/dementia. In our analysis, we will focus on genetic variants which activate pathways which can be targeted by drugs already available in clinical practice. This work will facilitate both prediction of future risk and the design
of novel therapeutic strategies which aim to prevent cognitive decline and eventual dementia in a short time frame.

1c: We will assess the possible causal relationship between genetic variants that are known to affect circulating levels of inflammatory markers with measures of cognitive function. Previous research has identified several genetic variants robustly associated with circulating levels of inflammatory markers. These will be used to form genetic risk scores for several inflammatory pathways. The associations of cognitive function with each genetic score will suggest causal associations between lifelong differences in the inflammatory pathway and cognitive function. When sufficient hospital episodes involving dementia will become available, we will repeat analyses with this binary outcome.

1d: Due to the large variability of the results at the neurocognitive tests we expect that data from the full cohort will be required for this project

Project extension February 2019:

Observational studies suggest that inflammation increases the risk of dementia and cognitive impairment. However, whether inflammation is cause or consequence of poor cognitive function remains unknown. Many genetic variants produce lifelong differences in the circulating levels of inflammatory markers. These genetic variants can be used to form scores which can inform on the cumulative impact of each inflammatory marker on cognition. In this project, the association of the genetic scores affecting circulating levels of inflammatory markers with cognitive function will be investigated to assess whether inflammation is causally relayed to higher risk of cognitive impairment.

Among factors potentially explaining the association between inflammation and cognitive impairment, sleep has emerged as one of the most intriguing in the last few years, as observational studies have documented that poor sleep quality and longer or shorter sleep duration are related to both a greater inflammatory exposure and an increased risk of cognitive decline/dementia. It remains unclear, however, if sleep represents a confounder of the inflammation-cognition association, a mediator or upstream causal variable. We therefore request permission to extend the scope of our project to test the independent causal association of sleep with the risk of dementia and cognitive impairment.